Dysregulated Plasticity in Serotonin, Galanin, and Opioid Systems Contributes to Limbic Seizure Recruitment in Wistar Audiogenic Rat

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Abstract
The Wistar Audiogenic Rat (WAR) strain is a genetically selected model of reflex epilepsy, susceptible to mesencephalic and, following chronic stimulation, limbic seizures. In this study, we examined the molecular underpinnings of this seizure progression by assessing gene expression profiles of pre‐synaptic serotonergic components in Dorsal Raphe Nucleus (DRN) and post‐synaptic receptors in the Basolateral Amygdala (BLA), Central Amygdala (CeA), and Hippocampus (HIP). Concurrently, we evaluated mRNA expression of Galanin (Gal) and Prodynorphin (Pdyn) in the Supraoptic Nucleus (SON) and their respective receptors in the BLA, CeA, and HIP. WARs and control Wistar rats underwent a ten‐day audiogenic kindling (AK) protocol, involving twice‐daily exposure to a high‐intensity acoustic stimulus to induce seizures. WARs were sub‐grouped based on their behavioral phenotype (seizure scales) into limbic‐recruited seizures (LiR) and non‐limbic‐recruited (n‐LiR). Quantitative PCR analysis of brain micropunches revealed a significant failure of adaptive plasticity in WARs. Unlike control rats, which showed a robust upregulation of serotonergic (5‐HT‐ergic) components in the DRN in response to the chronic stress of the kindling protocol, WARs had a significantly blunted pre‐synaptic response. Rats that did not show limbic seizures showed compensatory upregulation of amygdala 5‐HT receptors, a mechanism that failed in rats that developed chronic seizures. Furthermore, WARs showed elevated hypothalamic galanin but reduced limbic receptor expression. The opioid system was also imbalanced, with an increase in the pro‐convulsant mu‐opioid receptor. Critically, Pdyn expression was strongly and negatively correlated with limbic seizure severity. Collectively, these findings suggest that the progression to limbic epilepsy, already demonstrated in behavioral and EEG protocols in this model, is driven by a widespread failure of plasticity across interconnected neuromodulatory networks, rather than a single molecular defect, highlighting novel targets for therapeutic intervention. image
Funding Information
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2014/50891‐1)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2019/05957‐8)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2019/27581‐0)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2024/01620‐7)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2024/15733‐8)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (309882/2020‐6)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (315564/2023‐7)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (408707/2018‐6)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (421434/2023‐6)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (465458/2014‐9)
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Financial Code 001)

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